Is Cognitive Functioning (Really) Impaired in Methamphetamine Users ?

[Chip (OP)]

https://www.nature.com/articles/npp2011276

Is Cognitive Functioning Really Impaired in Methamphetamine Users?
A Critical Review

16 November 2011

Abstract:

The prevailing view is that recreational methamphetamine use causes a broad range of severe cognitive deficits, despite the fact that concerns have been raised about interpretations drawn from the published literature. This article addresses an important gap in our knowledge by providing a critical review of findings from recent research investigating the impact of recreational methamphetamine use on human cognition. Included in the discussion are findings from studies that have assessed the acute and long-term effects of methamphetamine on several domains of cognition, including visuospatial perception, attention, inhibition, working memory, long-term memory, and learning. In addition, relevant neuroimaging data are reviewed in an effort to better understand neural mechanisms underlying methamphetamine-related effects on cognitive functioning.

In general, the data on acute effects show that methamphetamine improves cognitive performance in selected domains, that is, visuospatial perception, attention, and inhibition. Regarding long-term effects on cognitive performance and brain-imaging measures, statistically significant differences between methamphetamine users and control participants have been observed on a minority of measures. More importantly, however, the clinical significance of these findings may be limited because cognitive functioning overwhelmingly falls within the normal range when compared against normative data. In spite of these observations, there seems to be a propensity to interpret any cognitive and/or brain difference(s) as a clinically significant abnormality. The implications of this situation are multiple, with consequences for scientific research, substance-abuse treatment, and public policy.

Introduction:

Amphetamine is a class of compounds that includes drugs used for both medical and recreational purposes. Of this class, d-amphetamine and methamphetamine are approved in several countries to treat a variety of disorders, including attention-deficit hyperactive disorder (ADHD), narcolepsy, and obesity. Over the past two decades, however, excessive illicit amphetamine use has become a major global concern.

According to data from the United Nations Office on Drugs and Crime in 2008, amphetamine is used at rates higher than cocaine and heroin combined, and while use has stabilized somewhat in European, North American, and African countries, amphetamine is becoming increasingly popular in South and Central America and in the Near and Middle East (2008 Global ATS Assessment). Amphetamine use continues to be most prevalent in Oceania, North America, and East and Southeast Asia, where approximately 1–2% of the respective adult populations report annual use (2008 Global ATS Assessment). Like other illicit drug use, amphetamine use is associated with increased hospital admissions, treatment admissions, and arrests (Dobkin and Nicosia, 2009). In some countries, the perception of problems associated with the abuse of amphetamine has become so worrisome that drastic measures have been taken.

Terminology note: The terms 'abuse' and 'dependence', as they are used throughout this review, conform to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV-TR) and International Statistical Classification of Diseases and Related Health Problems (ICD-10) definitions of substance abuse and dependence. DSM-IV-TR and ICD-10 terminology are used to avoid the use of pejorative words and terminology that have multiple meanings.

In response to reports of precipitous increases in methamphetamine abuse, in 1996 the government of Thailand banned all uses of amphetamine, including those for medical purposes (Pilley and Perngparn, 1998). Other governments have also taken steps to restrict legal uses of amphetamine, although most have not been as extreme as those taken in Thailand. For example, in the United Kingdom and New Zealand, while d-amphetamine remains available for medical purposes, any use of methamphetamine (including medical use) has been banned.

There are several amphetamines used recreationally, including d-amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, and 3,4-methylenedioxymethamphetamine. Of these compounds, methamphetamine has generated the greatest amount of concern. Indeed, periodically there are statements in the scientific and popular literature attesting to methamphetamine's greater potency and 'addictive' potential, relative to other amphetamines. Such statements, however, are inconsistent with data collected in humans, which show that d-amphetamine and methamphetamine produce nearly identical physiological and behavioral effects (e.g., Martin et al, 1971; Sevak et al, 2009; Kirkpatrick et al, in press a).

One reason for the unfounded beliefs about the drugs might be related to the fact that methamphetamine is more readily available on the illicit market owing to its apparent easier synthesis. A quick search of the Internet can provide the surfer with dozens of 'How to make meth' recipes within minutes. According to these recipes and law enforcement personnel, methamphetamine can be 'easily' made from a few common products, the most important of which is the over-the-counter cold medication, pseudoephedrine. As a result, it is not surprising that methamphetamine is the most frequently abused amphetamine.

Methamphetamine abuse is associated with multiple deleterious medical consequences, including paranoia mimicking full-blown psychosis (Grelotti et al, 2010) and hypertensive crisis leading to stroke (Ho et al, 2009). While serious, such cases are rare, and entail the long-term use of extremely large doses. A more commonly described unfavorable effect associated with methamphetamine abuse is extreme tooth decay ('meth mouth'). Several reports describing this phenomenon have appeared in the scientific literature (for a review, see Hamamoto and Rhodus (2009)).

In general, researchers conclude that methamphetamine restricts salivary flow leading to xerostomia (dry mouth). Because xerostomia can increase the likelihood of plaque and dental caries (tooth decay), this condition might underlie the dramatic pictures of 'meth mouth' seen in the popular media. Xerostomia is a relatively common side effect associated with many widely used medications, including the popular antidepressant Duloxetine (Cymbalta) and the ADHD medication d-amphetamine (Adderall: combination of amphetamine and d-amphetamine mixed salts). Despite the fact that these medications are used daily and frequently prescribed—each year both are among the top 100 most prescribed drugs in the United States (Bartholow, 2010)—there are no published reports of dental problems associated with their use.

Given the structural and pharmacological similarities of methamphetamine and d-amphetamine, this suggests that the phenomenon of 'meth mouth' has less to do with the direct pharmacological effects of methamphetamine and more to do with non-pharmacological factors, ranging from poor dental hygiene to media sensationalism. Indeed, much of the evidence linking methamphetamine abuse and tooth decay is anecdotal; detailed investigations of the impact of methamphetamine abuse on dental health with suitable oral health assessments are lacking (ADA, 2005; Cretzmeyer et al, 2007; but see, Shetty et al, 2010).

Another frequently reported deleterious effect associated with methamphetamine abuse and dependence is cognitive impairment. Unlike the scant literature examining the effects of the drug on dental health, there is a burgeoning amount of information detailing the impact of methamphetamine on cognitive functioning. The dominant view is that illicit methamphetamine use causes a broad range of cognitive impairments (for a review, see Scott et al (2007)).

Important shortcomings of the research perpetuating this perspective have received only limited attention. For example, in many of the studies the performance of methamphetamine abusers did not differ from controls on the majority of cognitive tasks employed. Importantly, although methamphetamine abusers performed significantly worse than controls on some cognitive tasks, their performance remained within the age- and education-matched normal range. Furthermore, previous discussions of the impact of methamphetamine-related effects on human cognition have neglected data from research assessing the immediate effects of the drug on cognitive performance. These studies can provide crucial complementary information because they assess cognitive performance immediately before and after administration of the drug. The rationale for this approach is that if methamphetamine produces cognitive deficits, one might predict that methamphetamine-induced disruptions would be observed following acute administration of large doses.

This article addresses an important gap in our knowledge by providing a critical review of findings from recent research investigating the impact of recreational methamphetamine use on human cognition. The discussion of methamphetamine on cognition is divided into three main categories: (1) the acute effects that occur shortly after the drug has been administered and are assessed while the drug is still in the body; (2) the long-term effects of repeated use that are typically assessed when the drug is no longer in the body; and (3) finally, relevant neuroimaging data will be evaluated in an effort to shed light on the neural mechanisms underlying methamphetamine-related effects on cognitive functioning. The review begins with a brief overview of methamphetamine neuropharmacology.

Conclusions:

For more than a decade, research investigating the effects of methamphetamine use on human cognition has steadily increased. Diverse methodologies have been employed, including basic human laboratory studies, during which the acute effects of the drug on cognitive performance are assessed, and studies that combine brain imaging with neuropsychological evaluation. In general, the human laboratory data show that short-term, acute methamphetamine improves cognitive performance of both methamphetamine abusers and non-users in some domains, for example, visuospatial perception, sustained attention, and response speed, even when larger intranasal and intravenous doses are tested. Although enhanced cognitive performance was not observed in a few studies, it is important to note that methamphetamine-induced disruptive cognitive effects were not observed and therefore rarely reported. It is possible that if larger doses, administered repeatedly, had been studied, more negative effects on cognition would have been observed. This would not be surprising given that it is true with other psychoactive agents, including the legal recreational drugs, alcohol, and caffeine. Note, however, that most of the doses tested in the laboratory studies were within the range needed to induce euphoria in the natural setting. Nonetheless, a more comprehensive understanding of the acute effects of methamphetamine on cognition would require testing of larger doses.

With regard to brain-imaging studies, several researchers have reported neural differences between methamphetamine users and control participants. One consistent PET finding was lower striatal DAT density in methamphetamine users. Data from MRI and fMRI studies also revealed some differences in brain structure volume and integrity, and activity differences, between the groups, but there have been few replications of specific findings among studies. This is a crucial factor to consider when reading studies that purport to have identified regional differences between methamphetamine-using participants and controls because such findings might be spurious and unrelated to methamphetamine use. In addition, despite the fact that most neuroimaging studies included only limited cognitive measures and despite the fact that cognitive functioning of methamphetamine users generally fell within the normal range, researchers frequently interpreted any brain differences as indicative of cognitive pathologies caused by the abuse of methamphetamine.

Studies solely focused on assessing the cognitive functioning of abstinent methamphetamine users are plagued by similar interpretation concerns. That is, even though methamphetamine users' performance overwhelmingly remained within the normal range, most researchers concluded that they showed evidence of global cognitive impairments (the dysfunction meaning of 'impairment'). For example, the findings of Simon et al (2002) led them to warn:

"The national campaign against drugs should incorporate information about the cognitive deficits associated with methamphetamine. Law enforcement officers and treatment providers should be aware that impairments in memory and in the ability to manipulate information and change points of view (set) underlie comprehension

... methamphetamine abusers will not only have difficulty with inferences but that they also may have comprehension deficits...

the cognitive impairment associated with [methamphetamine abuse] should be publicized."

Such warnings were based on measures that revealed statistically significant differences between methamphetamine users and controls, which alone are insufficient to determine true cognitive dysfunctions. Nevertheless, the apparent methamphetamine abuse-cognitive impairment link has been widely publicized—numerous articles have appeared in scientific journals and the popular press—despite the fact that it is not supported by evidence from research.

Implications:

Many researchers in this area begin with the assumption that methamphetamine abusers exhibit cognitive dysfunction, and that their research bears this out. Findings from this review suggest that this assumption should be re-evaluated to document the actual pattern of cognitive effects caused by the drug. For example, this prevailing assumption has provided the fuel for a growing number of neuroimaging studies assessing the impact of prenatal methamphetamine exposure. Hopefully, more caution will be exercised when interpreting these findings than was exercised when results were interpreted from studies of infants prenatally exposed to cocaine, who were erroneously and too readily condemned to a life of learning disabilities, psychological disturbances, and crime.

From a substance-abuse treatment perspective, it has been suggested that cognitive impairments seen in methamphetamine users have the potential to compromise their ability to engage in, and benefit from, cognitive-behavioral therapy, arguably the most effective treatment (Simon et al, 2002). Findings from this review argue that such concerns are not warranted.

Finally, from a public policy perspective, several governments have taken drastic measures in an effort to limit the use of methamphetamine, in part, because of the perceived pernicious effects the drug has on cognitive functioning. In Thailand, amphetamines are banned for all purposes—including medical. In the United States, methamphetamine-related violations are punished more harshly than those related to other illicit drugs, with the exception of crack cocaine. It is only recently that penalties associated with crack cocaine violations were reduced. This change came after nearly 25 years of criticism of the law because it was inconsistent with the scientific evidence and it exaggerated the harms associated with crack cocaine use. The monetary and human costs of this misunderstanding are incalculable.

As a final thought, note the parallel here: Many of the claims about methamphetamine-associated cognitive impairments are reminiscent of statements made about crack cocaine more than two decades ago before the empirical evidence was clear. Taken together, these observations lead us to speculate whether we are headed down this path once again.

NB: The full article is attached as a PDF: